The p38 MAP kinase signal transduction pathway is an important regulator of proinflammatory cytokine production and inflammation. Defining the roles of the various p38 family members, specifically p38␣ and p38␤, in these processes has been difficult. Here we use a chemical genetics approach using knock-in mice in which either p38␣ or p38␤ kinase has been rendered resistant to the effects of specific inhibitors along with p38␤ knock-out mice to dissect the biological function of these specific kinase isoforms. Mice harboring a T106M mutation in p38␣ are resistant to pharmacological inhibition of LPS-induced TNF production and collagen antibody-induced arthritis, indicating that p38␤ activity is not required for acute or chronic inflammatory responses. LPS-induced TNF production, however, is still completely sensitive to p38 inhibitors in mice with a T106M point mutation in p38␤. Similarly, p38␤ knock-out mice respond normally to inflammatory stimuli. These results demonstrate conclusively that specific inhibition of the p38␣ isoform is necessary and sufficient for anti-inflammatory efficacy in vivo.

No abstract

No abstract